Children and adolescents meeting DSM-III-R criteria for schizophrenia are being obtained through vigorous national recruiting. Thirty-eight subjects have participated to date in this study of the phenomenology, neurobiology and pharmacologic response of childhood onset schizophrenia. Over 700 medical records have been reviewed from which 165 patients and their families appearing to meet DSM-III-R criteria for schizophrenia with onset of psychosis prior to age 12, were screened in person. A total of 45 received the diagnosis of schizophrenia at screening. A large number of children are receiving the diagnosis of schizophrenia inappropriately resulting in inappropriate treatment, even at major academic centers. Our findings to date indicate continuity between childhood onset and later onset schizophrenia, with evidence that childhood onset schizophrenia may result from a more severe neurodevelopment lesion. Pilot family/genetic data indicate three cases (10%) are familial, not higher than seen with NIMH adult cases; a fourth subject had a 1:7 balance chromosomal translocation; a fifth subject had a microdeletion at 22q11; a sixth had 45-x0 (turners Syndrome). Three of 26 full siblings are mentally retarded. There is greater premorbid developmental delay particularly for language, than seen for the latter onset disorder. Autonomic and eye tracking measures parallel these of adult schizophrenia but may represent a more consistent and stronger pattern. MRI abnormalities resemble those results from adults, with a 9% smaller brain volume which is correlated with negative symptoms. A double-blind comparison of haloperidol and clozapine shows the superiority of clozapine for this very ill treatment refractory population. All subjects were pubertal by the time of admission, with no evidence of precocious puberty in any subject. Development of secondary sex characteristics was related to onset of psychosis in girls but not in boys. Cerebral glucose metabolism during performance of the auditory CPT in a subset of subjects age 12 or older indicated hypofrontalilty which was related to negative symptoms but which was not more severe that that seen in later onset schizophrenia. Childhood onset schizophrenics have a more significant general failure of brain development which may be of evidence of very early onset illness.